Meta-analysis of the efficacy and safety of finerenone in diabetic kidney disease

Background: The Phase III clinical trial of the non-steroidal mineralocorticoid receptor antagonist finerenone (BAY 94-8862) has been completed, aiming to investigate renal and cardiovascular (CV) outcomes in type 2 diabetes (T2D) with chronic kidney disease (CKD). However, the efficacy and safety of finerenone in renal function remain controversial. The purpose of this study was to explore the efficacy and safety of finerenone in treating the patients with diabetic kidney disease (DKD). Methods: Databases of PubMed, Cochrane Library, Embase, and Web of Science were searched for randomized controlled trials (RCTs) on patients with DKD receiving finerenone treatment from inception to September 2021. Data including patient characteristics and interested outcomes were extracted, and the dichotomous data and continuous variables were evaluated using risk ratio (RR) with 95% confidence intervals (CIs) and mean differences (MD) with 95% CIs, respectively. Results: A total of 4 RCTs involving 13945 patients were included in this meta-analysis. Analysis results demonstrated that patients receiving finerenone showed a significant decrease in changing urinary albumin-to-creatinine ratio (UACR) from baseline (MD: ﹣0.30; 95%CI [﹣0.33, ﹣0.27] P=0.46, I2=0%) (P＜0.05). The number of patients with ≥40% reduction in estimated glomerular filtration rate (eGFR) from baseline in the finerenone group was significantly smaller than that in the placebo group (RR: 0.85; 95%CI [0.78, 0.93] P=0.60, I2=0%) (P＜0.05). No difference was found in adverse events between the finerenone and placebo groups (RR: 1.00; 95%CI [0.98, 1.01] P = 0.94, I2=0%) (P=0.65). The incidence of hyperkalemia was higher in the finerenone group than that in the placebo group (RR: 2.03; 95%CI [1.83, 2.26] P = 0.95, I2=0%) (P＜0.05). Conclusion: Finerenone contributes to the reduction of UACR and can ameliorate the deterioration of renal function in patients with T2D and CKD. The higher risk of hyperkalemia was found in the finerenone group compared with placebo, however, there was no difference in the risk of overall adverse events.

Serum potassium disorders predict subsequent kidney injury: a retrospective observational cohort study of hospitalized patients

Introduction Electrolytes disorders are common findings in kidney diseases and might represent a useful biomarker preceding kidney injury. Serum potassium [K+] imbalance is still poorly investigated for association with acute kidney injury (AKI) and most evidence come from intensive care units (ICU). The aim of our study was to comprehensively investigate this association in a large, unselected cohort of hospitalized patients. Methods: We performed a retrospective observational cohort study on the inpatient population admitted to Fondazione Policlinico Universitario A. Gemelli IRCCS between January 1, 2010 and December 31, 2014 with inclusion of adult patients with at least 2 [K+] and 3 serum creatinine (sCr) measurements who did not develop AKI during an initial 10-day window. The outcome of interest was in-hospital AKI. The exposures of interest were [K+] fluctuations and hypo (HoK) and hyperkalemia (HerK). [K+] variability was evaluated using the coefficient of variation (CV). Cox proportional hazards regression models were used to obtain hazard ratios (HRs) and 95% confidence intervals (CIs) of the association between the exposures of interest and development of AKI. Results: 21,830 hospital admissions from 18,836 patients were included in our study. During a median follow-up of 5 (interquartile range [IQR] 7) days, AKI was observed in 555 hospital admissions (2.9%); median time for AKI development was 5 (IQR 7) days. Higher [K+] variability was independently associated with increased risk of AKI with a statistically significant linear trend across groups (p-value = 0.012). A significantly higher incidence of AKI was documented in patients with HerK compared with normokalemia. No statistically significant difference was observed between HoK and HerK (p-value = 0.92). Conclusion: [K+] abnormalities including fluctuations even within the normal range are associated with development of AKI.

Ulinastatin improves renal microcirculation by protecting endothelial cells and inhibiting autophagy in a septic rat model

Introduction: Increased permeability of the renal capillaries is a common consequence of sepsis-associated acute kidney injury. Vascular endothelial (VE)-cadherin is a strictly endothelial-specific adhesion molecule that can control the permeability of the blood vessel wall. Additionally, autophagy plays an important role in maintaining cell stability. Ulinastatin, a urinary trypsin inhibitor, attenuates the systemic inflammatory response and visceral vasopermeability. However, it is uncertain whether ulinastatin can improve renal microcirculation by acting on the endothelial adhesion junction. Methods: We observed the effect of ulinastatin in a septic rat model using contrast-enhanced ultrasonography (CEUS) to evaluate the perfusion of the renal cortex and medulla. Male adult Sprague-Dawley rats were subjected to cecal ligation and puncture and divided into the sham, sepsis, and ulinastatin groups. Ulinastatin (50,000 U/kg) was injected into the tail vein immediately after the operation. The CEUS was performed to evaluate the renal microcirculation perfusion at 3, 6, 12, and 24 hours after the operation. Histological staining was used to evaluate kidney injury scores. Western blot (WB) was used to quantify the expression of VE-cadherin, LC3II, and inflammatory factors [interleukin -1β (IL-1β), interleukin -6 (IL-6), and tumor necrosis factor-α (TNF-α)] in kidney tissue, and enzyme-linked immunosorbent assay (ELISA) detected serum inflammatory factors and kidney function and early kidney injury biomarker levels. Results: Compared with the sham group, ulinastatin reduced the inflammatory response, inhibited autophagy, maintained the expression of VE-cadherin, and meliorated cortical and medullary perfusion. Conclusion: Ulinastatin effectively protects the adhesion junction and helps ameliorate the perfusion of kidney capillaries during sepsis by the inhibition of autophagy and the expression of inflammatory factors.

Circulating miRNAs in Type 2 Diabetic Patients with and without Albuminuria in Malaysia

<b><i>Introduction:</i></b> Diabetic kidney disease (DKD) remains the leading cause of chronic kidney disease. Dysregulation of circulating miRNAs has been reported, suggesting their pathological roles in DKD. This study aimed to investigate differentially expressed miRNAs in the sera of type 2 diabetes mellitus (T2DM) patients with and without albuminuria in a selected Malaysian population. <b><i>Method:</i></b> Forty-one T2DM patients on follow-up at a community clinic were divided into normo-(NA), micro-(MIC), and macroalbuminuria (MAC) groups. Differential levels of miRNAs in 12 samples were determined using the pathway-focused (human fibrosis) miScript miRNA qPCR array and was validated in 33 samples, using the miScript custom qPCR array (CMIHS02742) (Qiagen GmbH, Hilden, Germany). <b><i>Results:</i></b> Trends of upregulation of 3 miRNAs in the serum, namely, miR-874-3p, miR-101-3p, and miR-145-5p of T2DM patients with MAC compared to those with NA. Statistically significant upregulation of miR-874-3p (<i>p</i> = 0.04) and miR-101-3p (<i>p</i> = 0.01) was seen in validation cohort. Significant negative correlations between the estimated glomerular filtration rate (eGFR) and miR-874-3p (<i>p</i> = 0.05), miR-101-3p (<i>p</i> = 0.03), and miR-145-5p (<i>p</i> = 0.05) as well as positive correlation between miR-874-3p and age (<i>p</i> = 0.03) were shown by Pearson’s correlation coefficient analysis. <b><i>Conclusion:</i></b> Upregulation of previously known miRNA, namely, miR-145-5p, and possibly novel ones, namely, miR-874-3p and miR-101-3p in the serum of T2DM patients, was found in this study. There was a significant correlation between the eGFR and these miRNAs. The findings of this study have provided encouraging evidence to further investigate the putative roles of these differentially expressed miRNAs in DKD.

Acute Kidney Injury at Hospital Admission for SARS-CoV-2 Infection as a Marker of Poor Prognosis: Clinical Implications for Triage Risk Stratification

<b><i>Background/Aims:</i></b> The new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a wide spectrum of effects, including acute kidney injury (AKI) in up to 40% of hospitalized patients. Given the established relationship between AKI and poor prognosis, whether AKI might be a prognostic indicator for patients admitted to the hospital for SARS-CoV-2 infection would allow for a straightforward risk stratification of these patients. <b><i>Methods:</i></b> We analyzed data of 623 patients admitted to San Raffaele Hospital (Milan, IT) between February 25 and April 19, 2020, for laboratory-confirmed SARS-CoV-2 infection. Incidence of AKI at hospital admission was calculated, with AKI defined according to the KDIGO criteria. Multivariable Cox regression models assessed the association between AKI and overall mortality and admission to the intensive care unit (ICU). <b><i>Results:</i></b> Overall, 108 (17%) patients had AKI at hospital admission for SARS-CoV-2 infection. After a median follow-up for survivors of 14 days (interquartile range: 8, 23), 123 patients died, while 84 patients were admitted to the ICU. After adjusting for confounders, patients who had AKI at hospital admission were at increased risk of overall mortality compared to those who did not have AKI (hazards ratio [HR]: 2.00; <i>p</i> = 0.0004), whereas we did not find evidence of an association between AKI and ICU admission (HR: 0.95; <i>p</i> = 0.9). <b><i>Conclusions:</i></b> These data suggest that AKI might be an indicator of poor prognosis for patients with SARS-CoV-2 infection, and as such, given its readily availability, it might be used to improve risk stratification at hospital admission.

Lung ultrasound as tool to evaluate fluid accumulation in dialysis patients

Background: Volume overload is the main mechanism of BP elevation in end-stage kidney disease (ESKD) patients undergoing hemodialysis or peritoneal dialysis and has been linked to adverse outcomes and increased mortality in this population. Summary: This review discusses current knowledge on lung ultrasound as a tool for detection of extracellular volume overload through evaluation of extravascular lung water content. We describe the principles of lung US, the main protocols to apply it in clinical practice, and accumulated data evidence regarding its associations with cardiovascular events and mortality. We also summarize available evidence on the effect of lung-ultrasound guided volume management strategies on BP control, echocardiographic parameters and major outcomes in patients undergoing dialysis. Key Messages: Among interventions attempting to reduce the burden of cardiovascular disease in ESKD, effective management of volume overload represents an unmet clinical need. Assessment of hydration status by lung-ultrasound is a cheap, easy to employ and real-time technique that can offer accurate dry weight assessment leading to several clinical benefits.

Association between Cardiac Outcomes and Indoxyl Sulfate Levels in Hemodialysis Patients: A Cross-sectional Study

Objective Indoxyl sulfate (IS) is a protein-bound uremic toxin that is associated with cardiovascular events and mortality in hemodialysis (HD) patients. However, the factors affecting the levels of IS are currently unclear. This study aimed to investigate the factors influencing serum IS concentrations in HD patients. Methods We included 100 HD patients from Guangdong Provincial People’s Hospital. Baseline characteristics, including sex, age, clinical features, duration of HD, echocardiography findings, electrocardiogram results, and biochemical indicators, were collected and analyzed in relation to serum total-form IS levels. Results Among all 100 patients, serum IS levels were significantly higher in patients aged ≥ 60 years, males, and patients with mitral regurgitation and inadequate dialysis. Among patients aged < 60 years, IS levels were significantly higher among patients with mitral regurgitation compared with those without. Furthermore, multiple linear regression analysis identified sex, age, ventricular septal thickness, and mitral regurgitation as factors independently associated with serum IS (STDβ = −0.475, 0.162, −0.153, 0.142, and 0.136, respectively; all P < 0.05) adjusted for body mass index, smoking, and fasting plasma glucose. Conclusions Male sex, age ≥ 60 years, ventricular septal thickness, and mitral regurgitation are factors associated with high total serum IS concentrations in Chinese HD patients. Elevated IS levels may play a role in the process of mitral regurgitation in HD patients < 60 years old.

Endurance exercise training-attenuated diabetic kidney disease with muscle weakness in spontaneously diabetic Torii fatty rats.

Background The aim of this study was to evaluate protective effects of endurance exercise training against diabetic kidney disease (DKD) with muscle weakness by using male spontaneously diabetic Torii (SDT) fatty rats as type 2 diabetic animal models with obesity, hypertension, and hyperlipidemia. Methods Eight-week-old SDT fatty rats (n = 12) and Sprague–Dawley (SD) rats (n = 10) were randomly divided into exercise (Ex; SDT-Ex: n = 6, SD-Ex: n = 5) and sedentary groups (SDT-Cont: n = 6, SD-Cont: n = 5), respectively. Each group underwent regular treadmill exercise four times a week from ages 8 to 16 weeks. Results The exercise attenuated hypertension and hyperlipidemia and prevented increases in renal parameter levels without affecting blood glucose levels. In the SDT fatty rats, it prevented induction of renal morphological abnormalities in the interstitium of the superficial and intermediate layers of the cortex. Downregulated expression of endothelial nitric oxide synthase in the glomerulus of the SDT fatty rats was significantly upregulated by the exercise. The exercise upregulated the renal expressions of both medium-chain acyl-CoA dehydrogenase and peroxisome proliferator-activated receptor γ coactivator-1α related to fatty acid metabolism. It increased muscle strength and both muscle weight and cross-sectional area of type IIb muscle fibers in the extensor digitorum longus muscle in the SDT fatty rats. Conclusion Endurance exercise training in type 2 diabetes ameliorates DKD by improving endothelial abnormality and enhancing fatty acid metabolism in addition to attenuated hypertension, hyperlipidemia, and muscle weakness independently of blood glucose levels.

Hemodialysis Patients with Cardiovascular Disease Reveal Increased Tissue Na+ Deposition

Background: The relationship between Na+ balance and cardiovascular disease (CVD) in hemodialysis (HD) patients is not yet fully understood. We hypothesized that HD patients co-diagnosed with CVD show increased tissue Na+ accumulation compared to HD patients without CVD. Methods: In our observational study 52 HD patients were divided into a group with (23 subjects) or without (29 subjects) a positive history of cardiovascular events. We used 23Na-Magnetic Resonance Imaging (23Na-MRI) at 3.0 Tesla to quantify Na+ content in skin and muscle of both groups directly before and after HD. Additionally, total body fluid distribution was determined by Bioimpedance Spectroscopy (BIS) and laboratory parameters were assessed. Results: Compared to HD patients without CVD, 23Na-MRI detected an increased Na+ content in skin (21.7 ± 7.3 vs. 30.2 ± 9.8 arbitrary units, a.u., p < 0.01) and muscle tissue (21.5 ± 3.6 vs 24.7 ± 6.0 a.u., p < 0.05) in patients with previous CVD events. Simultaneously measured fluid amount by BIS, including excess extracellular water (1.8 ± 1.7 vs. 2.2 ± 1.7 L, p = 0.44), was not significantly different between both groups. Tissue Na+ accumulation in HD-CVD patients was paralleled by a higher plasma concentration of the inflammation marker Interleukin-6 (5.1, IQR 5.8 vs. 8.5, IQR 7.9 pg/ml, p < 0.05). Conclusion: In our cohort, HD patients with CVD showed higher tissue Na+ content than HD patients without CVD, while no difference in body water distribution could be detected between both groups. Our findings provide evidence that the history of a cardiovascular event is associated with disturbances in tissue Na+ content in HD patients.

The 370 Da inhibitor of the sodium pump in the plasma of haemodialysis patients

Background: Previous studies have shown that a molecule of mass 370 Da that inhibits the sodium pump can be extracted from human placentas and from the concentrated plasma or ultrafiltrate of volume-expanded patients. Aim: To study the abundance of the 370 Da molecule and its changes across dialysis in a population of patients with renal failure treated by haemodialysis. Methods: 4 mL pre- and post-dialysis blood samples (2 mL plasma) were taken from patients receiving intermittent haemodialysis and analysed by high performance liquid chromatography (HPLC) coupled to high sensitivity mass spectrometry. Results: In over half the study population, the 370 Da molecule was present in an abundance that exceeded the limit of quantitation. Most patients experienced a marked fall in the abundance of the molecule over a haemodiafiltration (HDF) session, though exceptions were seen in two individuals both of whom showed clear evidence for the presence of two structural isomers of the 370 Da molecule. Conclusions: Advanced renal failure is frequently accompanied by an increased abundance of a 370 Da inhibitor of the sodium pump and that abundance is strongly impacted by haemodialysis. The technique described here could readily be applied to other clinical situations where sodium pump inhibition might be anticipated, such as hypertension, pregnancy and fetal medicine and thereby lead to a better understanding of the physiology and patho-physiology of these conditions.